In 1966 Mitchell joined the manned space program. During the 1970 Apollo 13 mission, when an oxygen tank explosion damaged the spacecraft, Mitchell worked in the lunar module simulator at the Lyndon B. Johnson Space Center in Houston to develop procedures for the safe return of the spacecraft and its crew. He received (1970) a Presidential Medal of Freedom for his work. During the Apollo 14 mission, Mitchell, Shepard, and Roosa, set records for the most time (33 hours) and longest distance traversed on the lunar surface. They also collected 42.6 kg (94 pounds) of rock and soil samples to be studied.

In 1972 Mitchell retired from the navy and the space program. His interest in parapsychology led him to found (1973) the Institute of Noetic Sciences in Palo Alto, California. He wrote The Way of the Explorer (1996), about his experiences as an astronaut and his spiritual journey.